title: Acceleration of tuberculosis treatment by adjunctive therapy with verapamil as an efflux inhibitor.
abstract: BACKGROUND
  A major priority in tuberculosis (TB) is to reduce effective treatment times and emergence of resistance. Recent studies in macrophages and zebrafish show that inhibition of mycobacterial efflux pumps with verapamil reduces the bacterial drug tolerance and may enhance drug efficacy.
  
  
  OBJECTIVE
  Using mice, a mammalian model known to predict human treatment responses, and selecting conservative human bioequivalent doses, we tested verapamil as an adjunctive drug together with standard TB chemotherapy. As verapamil is a substrate for CYP3A4, which is induced by rifampin, we evaluated the pharmacokinetic/pharmacodynamic relationships of verapamil and rifampin coadministration in mice.
  
  
  METHODS
  Using doses that achieve human bioequivalent levels matched to those of standard verapamil, but lower than those of extended release verapamil, we evaluated the activity of verapamil added to standard chemotherapy in both C3HeB/FeJ (which produce necrotic granulomas) and the wild-type background C3H/HeJ mouse strains. Relapse rates were assessed after 16, 20, and 24 weeks of treatment in mice.
  
  
  RESULTS
  We determined that a dose adjustment of verapamil by 1.5-fold is required to compensate for concurrent use of rifampin during TB treatment. We found that standard TB chemotherapy plus verapamil accelerates bacterial clearance in C3HeB/FeJ mice with near sterilization, and significantly lowers relapse rates in just 4 months of treatment when compared with mice receiving standard therapy alone.
  
  
  CONCLUSIONS
  These data demonstrate treatment shortening by verapamil adjunctive therapy in mice, and strongly support further study of verapamil and other efflux pump inhibitors in human TB.
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Shashank
authors.initials: S
authors.lastname: Gupta
authors.forename: Sandeep
authors.initials: S
authors.lastname: Tyagi
authors.forename: Deepak V
authors.initials: DV
authors.lastname: Almeida
authors.forename: Mariama C
authors.initials: MC
authors.lastname: Maiga
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Ammerman
authors.forename: William R
authors.initials: WR
authors.lastname: Bishai
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D051379:Mice; D008809:Mice, Inbred C3H; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D012008:Recurrence; D012293:Rifampin / Q000008:administration & dosage / Q000627:therapeutic use*; D013997:Time Factors; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*; D014700:Verapamil / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D000277:Adjuvants, Pharmaceutic; D000995:Antitubercular Agents; D002121:Calcium Channel Blockers; D014700:Verapamil; D012293:Rifampin